Resistance to RET inhibitors appears to more frequently result from the recruitment of compensatory signalling pathways such as MET and KRAS as opposed to a resistance mutation in RET itself.^1,2 One potential approach to delay resistance is to focus on combining RET inhibitor therapy with other agents targeting alternative signalling pathways.²

Abbreviation

RET, rearranged during transfection.

References

1. Lin JJ, Gainor JF. J Clin Oncol. 2022;41:410–3.
2. Rocco D, et al. Int J Mol Sci. 2023;24:2433.

The RET inhibitors pralsetinib and selpercatinib are both approved for use in RET-positive NSCLC.^1,2 The phase I/II ARROW trial investigated pralsetinib (400 mg QD) in treatment-naive and pre-treated patients with RET-positive NSCLC. This study found an ORR of 72% in treatment-naive patients (n=75).³

LIBRETTO-001 was a phase I/II trial investigating the use of selpercatinib (160 mg BID) in treatment-naive and pretreated patients. This study found an ORR of 83% in treatment-naive patients (n=69).⁴ These data were also reflected in the phase III LIBRETTO-431 trial in patients receiving first-line selpercatinib (160 mg BID) which found an ORR of 84% in patients receiving selpercatinib (n=159).⁵

Abbreviations

BID, twice daily; NSCLC, non-small cell lung cancer; ORR, objective response rate; QD, once daily; RET, rearranged during transfection.

References

1. FDA. Selpercatinib PI. Available at: www.accessdata.fda.gov/drugsatfda_docs/label/2024/213246s014lbl.pdf (accessed 2 May 2025).
2. FDA. Pralsetinib PI. Available at: www.accessdata.fda.gov/drugsatfda_docs/label/2024/213721s015lbl.pdf (accessed 2 May 2025).
3. Griesinger F, et al. Ann Oncol. 2022;33:1168–78.
4. Gautschi O, et al. J Clin Oncol. 2025; DOI:10.1200/JCO-24-02076 [Online ahead of print].
5. Zhou C, et al. N Engl J Med. 2023;389:1839–50.

The NCCN guidelines recommend testing for EFGR, KRAS, ALF, ROS1, BRAF, NTRK, MET, RET, HER2, NRG1 and PD-L1 in patients with NSCLC to identify actionable genomic alterations.¹ RNA testing is typically used to detect fusions.² RNA-based NGS is the first choice testing for RET detection based on better sensitivity, specificity and ability to detect the fusion partner and expression level of gene fusion. DNA NGS assays have a more limited sensitivity for the detection of fusion genes due to the need for proper optimization of the panel to include intronic regions.³

Abbreviations

EGFR, epidermal growth factor receptor; NCCN, National Comprehensive Cancer Network; NGS, next-generation sequencing; NSCLC, non-small cell lung cancer; PD-L1, programmed death-ligand 1; RET, rearranged during transfection.

References

1. NCCN Clinical Practice Guidelines in Oncology. Non-Small Cell Lung Cancer Version 3.2025 – 14 January 2025. Available at: NCCN.org (accessed 25 April 2025).
2. Ionescu DN, et al. Curr Oncol. 2022;29:4981–97.
3. Novello S, et al. The Oncologist. 2023;28:402–13.

The NCCN guidelines recommend treatment with pralsetinib or selpercatinib in patients with NSCLC and RET fusions;¹ evidence suggests suboptimal responses to immunotherapy in these patients, as they have low tumour mutation load and low PD-L1 expression.²

Hypertension, increased AST and ALT, and QTc prolongation are among the most frequent (≥10%) grade ≥3 TRAEs for patients receiving selpercatinib, based on the LIBERETTO-001 and LIBRETTO-431 clinical trials.^3,4 Conversely, the most frequent (≥10%) grade ≥3 TRAEs reported in patients receiving pralsetinib, based on the phase I/II ARROW trial, are neutropenia, anemia and hypertension.⁵ Of note, real-world and clinical trial evidence suggests that QT interval prolongation is an AE observed exclusively in patients receiving selpercatinib; no such AEs were reported for pralsetinib cohort.⁶ Thus, additional monitoring would be required if selpercatinib is selected in patients at risk of developing QTc prolongation, such as patients with uncontrolled heart failure.⁷

Abbreviations

AE, adverse event; ALT, alanine aminotransferase; AST, aspartate aminotransferase; NCCN, National Comprehensive Cancer Network; NSCLC, non-small cell lung cancer; RET, rearranged during transfection; TRAE, treatment-related AE.

References

1. NCCN Clinical Practice Guidelines in Oncology. Non-Small Cell Lung Cancer Version 3.2025 – 14 January 2025. Available at: NCCN.org (accessed 25 April 2025).
2. Novello S, et al. Oncologist. 2023;28:402–13.
3. Gautschi O, et al. J Clin Oncol. 2025; DOI:10.1200/JCO-24-02076 [Online ahead of print].
4. Zhou C, et al. N Engl J Med. 2023;389:1839–50.
5. Griesinger F, et al. Ann Oncol. 2022;33:1168–78.
6. Jie Q, et al. Front Pharmacol. 2024;15:1424980.
7. FDA. Selpercatinib PI. Available at: www.accessdata.fda.gov/drugsatfda_docs/label/2024/213246s014lbl.pdf (accessed 25 April 2025).

The NCCN guidelines state that if RET rearrangement is discovered during first-line systemic therapy for NSCLC, the current therapy should be interrupted and treatment with pralsetinib or selpercatinib should begin.¹ Both drugs have shown efficacy and their safety profiles show similarities in severity and tolerability but, as noted earlier, additional monitoring for QT prolongation in patients on selpercatinib is recommended, whereas patients on pralsetinib may be at increased risk of interstitial lung disease or pneumonitis.² Data suggest that selpercatinib may be favoured in patients with underlying respiratory comorbidities, due to lower incidence of pneumonitis.³

Abbreviations

NCCN, National Comprehensive Cancer Network; NSCLC, non-small cell lung cancer; RET, rearranged during transfection.

References

1. NCCN Clinical Practice Guidelines in Oncology. Non-Small Cell Lung Cancer Version 3.2025 – 14 January 2025. Available at: NCCN.org (accessed 25 April 2025).
2. Nguyen VQ, Geirnaert M. J Oncol Pharm Pract. 2022;29:450–6.
3. Sacchi de Camargo Correia G, et al. J Thorac Oncol. 2024;19(Suppl):S644.